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It is often meaningful to obtain the partition coefficients of molecules by calculation. The molecular structure and extent of ionization are the primary factors in calculating the partition coefficient. The standard partition coefficient of ionized and unionized species calculated from the molecular structure is based largely on the atomic logP increments given in Viswanadhan et al. The extent of ionization at a given pH is obtained from the predicted pKa of the molecule. Our calculation method takes into account the effect of the counterion concentration on logD and logP. 

Symbols used

Throughout the document we use the following symbols:

 

Definition of logand logD
 

The partition coefficient is the ratio of the concentration of the compound in octanol to its concentration in water. The distribution coefficient is the ratio of the sum of the concentrations of all species of the compound in octanol to the sum of the concentrations of all species of the compound in water. Based on acidic/basic dissociation reactions, we can introduce the concept of a partition coefficient for cationic and anionic species and for neutral species.

The following figure gives the definition of partition and distribution coefficients for ionized and unionized species. 

 

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fig.1
fig.1

 
Fig. 1 Partition and distribution coefficients for ionized and unionized species

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  • Partition coefficient of the neutral species is

     
  • Partition coefficients of the anionic and the cationic species are

     
    and 

  • Distribution coefficient of the original molecule is

The micro partition coefficient is the ratio of the concentration of two microspecies defined with pi as expressed with the next relation: 

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Relation between macro and micro partition coefficients

 

Macro partition coefficients P0…Pi can also be expressed as a function of micro partition coefficients p0…piFrom the definition of micro partition coefficients we obtain the following formula for the concentration of microspecies in octanol: 

[microspecies]i,octanol = pi ⋅[microspecies]i,water 

 
where pi is the micro partition coefficient of microspecies i

For example, P-1 includes four micro partition coefficients (p1, p2, p3, p4). They are given by the following formulae:

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After substituting the pis into the original formula for P-1 we get the following simpler formula which includes only aqueous concentration of the appropriate microspecies:

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This can be further simplified if we introduce the acid dissociation constants of the A1A2B1B2 molecule. The next five ionization reactions of the A1A2B1B2 molecule are used to rearrange P-1 into a concentration free form:

Image Modified

So we can further simplify the formula for P-1 to the following. This expression reveals that P-1 does not depend on the pH of the solution: 
Image Modified 

Similarly, one could show that P0P+1, P-2 and P+2 are also pH-independent.

In contrast to this, the distribution coefficient D does depend on the solution pH (see 
Klopman et al.):

 


LogP calculation methods

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fig.5

 

Fig. 4 Homidium molecule


Example #3

 

Ibuprofen has the typical logD vs. pH profile that is characteristic of acidic compounds. Lipophilic behavior of ibuprofen will be dominant when its carboxylic group is unionized (at low pH). At higher pH values the carboxylic group reaches the fully ionized state and hydrofilicity becomes more enhanced. 

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Fig. 6 Ibuprofen and its logD-pH plot


Example #4

 

The measured distribution coefficients also depends on the measurement method. The shake flask and the pH-metric methods are the most popular in practice. The figure below shows the calculated and measured logD of lignocaine as function of pH. 

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Fig. 7 Lignocaine and its logD-pH plot

 


References

  1. Anchor
    viswan
    viswan
    Viswanadhan, V. N.; Ghose, A. K.; Revankar, G. R. and Robins, R. K., J.Chem.Inf.Comput.Sci.198929, 3, 163-172; 
    doi
  2. Anchor
    klopman
    klopman
    Klopman, G.; Li, Ju-Yun.; Wang, S.; Dimayuga, M.: J.Chem.Inf.Comput.Sci.199434, 752; 
    doi
  3. Anchor
    physprop
    physprop
    PhysProp© database, webpage
  4. Csizmadia, F.; Tsantili-Kakoulidou, A.; Panderi, I. and Darvas, F., J.Pharm.Sci.199786, 7, 865-871; doi
  5. Bouchard, G.; Carrupt, P. A.; Testa, B.; Gobry, V. and Girault, H. H., Pharm.Res.200118, 5, 702-708; doi